tbuckley/cabot-search huggingface dataset:
Abstract P2-21-06: The relationship between the gene expression difference of fibroblasts in the tumor microenvironment and metastasis of triple-negative breast cancer
Authors: Woo Hang Heo, Woochan Lee, SONGBIN LI, Jong-Il Kim, Hyeong-Gon Moon
Journal: Cancer Research (2023)

Abstract Background Triple negative breast cancer (TNBC) is a breast cancer subtype with increased risk of distant metastasis, especially to lung and liver. In addition to the intrinsic characteristics of tumor cells, the molecular features of the tumor microenvironment cells can also regulate the metastasis process of TNBC. In this study, we tried to characterize the transcriptomic features of microenvironment fibroblasts associated with the distant metastasis of TNBC. Method We established PDX models by obtaining tumor tissues from 26 triple-negative breast cancer patients and transplanting them into the mammary fat pads of immunodeficient mice. When the PDX tumors grew sufficiently in the fat pads, we excised them and saved the mice to assess whether each PDX tumor was capable of developing spontaneous distant metastasis. We used bulk RNA sequencing and single cell RNA sequencing to determine the transcriptomic features associated with the distant metastasis. Results We classified the 26 TNBC PDX models based on their in vivo metastasis capacity and the clinical outcomes of the corresponding patients. Non-metastatic PDX models were defined as the lack of developing distant metastasis in either mouse experiment or clinical follow-up data (n=5). PDX models were defined as metastatic models when they developed distant metastasis in both mouse and human (n=4). We performed single cell RNA sequencing using the nine PDX tumors and observed a substantial gene expression differences of fibroblasts in the tumor microenvironment between the metastatic and non-metastatic PDX models. The fibroblasts of the metastatic PDX models showed up-regulation of genes involved in the response to hypoxia, inflammatory response, neutrophil chemotaxis, cellular response to IL-1, positive regulation of cell proliferation, and negative regulation of apoptotic process. Moreover, this difference of gene expression between metastatic and non-metastatic TNBC PDX models were not identified by the bulk RNA sequencing data. Conclusion By using the single cell RNA sequencing using the TNBC PDX models, we identified key features of fibroblasts in the tumor microenvironment that contributes to the metastasis capacity of TNBC. Further studies are on-going to elucidate the underlying mechanisms. Citation Format: Woo Hang Heo, Woochan Lee, SONGBIN LI, Jong-Il Kim, Hyeong-Gon Moon. The relationship between the gene expression difference of fibroblasts in the tumor microenvironment and metastasis of triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-21-06.
Abstract P2-17-01: Targeted CRISPR screen to identify synthetic lethal combinations between APOBEC3B and DNA repair
Authors: Bojana Stefanovska, Kevin Lin, Benjamin Troness, Chad Myers, Reuben Harris
Journal: Cancer Research (2023)

Abstract APOBEC-catalyzed deamination of cytosine bases is the largest enzymatic and second largest overall source of mutation in cancer. One member from the APOBEC family of enzymes, APOBEC3B (A3B) is overexpressed and dysregulated in many different cancer types. In addition to hallmark C-to-T transitions and C-to-G transversions, APOBEC-catalyzed uracil lesions can be processed into single- and double-strand DNA breaks. Therefore, A3B-positive tumors are under continual stress to repair DNA breaks and may be vulnerable to DNA repair inhibition. Previous results from the Harris lab have identified UNG2, DNA uracil glycosylase 2 (UNG2), initiator of the base excision repair pathway, as synthetic lethal pair with A3B. The genetic disruption of UNG2 combined with high expression of A3B, causes cell death. This provides the rational to hypothesize that also other DNA repair proteins could be putative synthetic lethal pairs with A3B, when its expression and activity are high. To test this hypothesis, CRISPR guide RNA library targeting 237 DNA damage repair and response genes was used in doxycycline-inducible TREX-293-A3Bi-eGFP cell line. Cells expressing or not A3B were harvested for DNA extraction and sequencing at different time points. Comparison of guide RNA abundance between doxycycline and H2O treated cells revealed the dropout guides that disrupt genes and create putative synthetic lethal combinations with A3B. The screen design and overall results will be presented Citation Format: Bojana Stefanovska, Kevin Lin, Benjamin Troness, Chad Myers, Reuben Harris. Targeted CRISPR screen to identify synthetic lethal combinations between APOBEC3B and DNA repair [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-17-01.
Abstract OT1-20-01: SentiNot 2.0: Avoid unnecessary Sentinel Lymph Node Biopsies in women with DCIS
Authors: Eirini Pantiora, Staffan Eriksson, Lida Pistiolis, Roger Olofsson Bagge, Gyula Nagy, Alastair M. Thompson, Vivian Man, Ava Kwong, Andreas Karakatsanis, Fredrik Wärnberg
Journal: Cancer Research (2023)

Abstract Background Approximately 15-30% of women with a preoperative diagnosis of ductal carcinoma in situ (DCIS) will be diagnosed with invasive cancer (IBC) on specimen pathology. Risk of upgrade, and impairment of lymphatic outflow after breast surgery, mainly mastectomy, are drivers for upfront sentinel lymph node dissection (SLND). In the SentiNot feasibility study, marking the SLN by superparamagnetic iron oxide nanoparticles (SPIO) injection during primary surgery minimized unnecessary SLNDs, allowing for delayed SLND (d-SLND) only in those with IBC up to 50 days after primary surgery. This policy resulted in that 78.3% study participants avoided upfront SLND. In the d-SLND setting, SPIO detection outperformed the isotope (98.5 vs 60.6%), regardless of type of breast procedure. Incremental healthcare costs were reduced by 8.5% (485 USD per patient) for the entire trial population (ref 1). Prospective Clinical Trial Design SentiNot 2.0 (ClinicalTrials.gov Identifier: NCT04722692), is currently accruing data, powered to examine the detection rate of SPIO over isotope±blue dye during d-SLND. Trial candidates are: patients with a diagnosis of high-risk DCIS/pLCIS (mass-lesions, microinvasion, grade 3, grade 2 &amp;gt;20mm) regardless of type of breast surgery, and patients with planned breast surgery that precludes safe and accurate axillary mapping at a d-SLND (extensive oncoplastic breast conservation, tumors of the axillary tail and mastectomy). In d-SLND, study patients receive isotope±blue dye and within-patient-randomization is performed for which detection method to start with (SPIO-first vs. isotope-first). The trial is stratified for mastectomy and breast conservation. Secondary outcomes are nodal concordance (SPIO vs. isotope) at d-SLND, quality-of-life and health-economy outcomes. Present and Planned Accrual Total target accrual is 500 d-SLNDs. Insofar, 360 women have been included at six different sites in Sweden, Hong Kong, and the USA. Currently, data accrual and institution recruitment is active and expanding. For more information about the trial please refer to ClinicalTrials.gov Identifier: NCT04722692. For discussion regarding potential participation contact dr Andreas Karakatsanis (andreas.karakatsanis@surgsci.uu.se). Citation Format: Eirini Pantiora, Staffan Eriksson, Lida Pistiolis, Roger Olofsson Bagge, Gyula Nagy, Alastair M. Thompson, Vivian Man, Ava Kwong, Andreas Karakatsanis, Fredrik Wärnberg. SentiNot 2.0: Avoid unnecessary Sentinel Lymph Node Biopsies in women with DCIS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-20-01.
Abstract P2-17-02: SMC6 down-regulation: marker of genetic instability and poor outcome in breast cancer
Authors: Flavia R. Rotea Mangone, Ana Cristina V. Krepischi, Dirce M. Carraro, Maria A. Nagai
Journal: Cancer Research (2023)

Abstract Genetic instability commonly found in tumors may be a consequence of imbalance in homologous recombination (HR), a mechanism of DNA double-strand break (DSB) repair dependent on the formation and resolution of Holliday junctions’ structures for genomic stability maintenance. The SMC6 is involved in DSB repair. The SMC6 gene is structurally located very close to the GEN1 gene in a head-to-head organization sharing a bi-directional promoter, and the encoded protein is also involved in HR. Herein, we explored the association between SMC6 expression, genomic instability, and prognosis of breast cancer (BC). SMC6 and GEN1 expression and Copy Number Variation (CNV) data measured by qRT-PCR and CGH array, respectively, were assessed in 33 BC of women non-carrier BRCA1/BRCA2-mutations. The SMC6 protein expression was evaluated on a Tissue Microarray containing 74 BC samples classified as low (negative/weak) or high (moderate/strong) according to SMC6 nuclear staining. SMC6 and GEN1 expressions were directly correlated (p=0.821). Moreover, SMC6-low tumors tend to show higher CNV. Yet, the SMC6-low group presented poorer disease-free survival (DFS) than the SMC6 high group (log-rank=0.008). Further, SMC6 expression broke the DFS ER+ cohort in groups of distinct prognoses (log-rank=0.029). By in silico data analysis, SMC6 downregulation was also associated with worse prognosis in some BC subtypes. Our findings point to a possible association between SMC6 down-regulation and BC poor outcomes, suggesting that SMC6 may serve as an indicator of tumor genetic instability for BC patients. Supported by Fapesp and CNPq. Citation Format: Flavia R. Rotea Mangone, Ana Cristina V. Krepischi, Dirce M. Carraro, Maria A. Nagai. SMC6 down-regulation: marker of genetic instability and poor outcome in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-17-02.
Abstract OT2-16-03: Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress)
Authors: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara C. O’Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras
Journal: Cancer Research (2023)

Abstract Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned. Citation Format: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara C. O’Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras. Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-03.
Abstract P2-11-30: Performance of tumor vascularity as a biomarker is correlated with the change of tumor vascularity after preoperative systemic treatment in patients with breast cancer
Authors: Hyang Suk Choi, Eun Ju Son, Hany Hany Noh, In-Jeong Cho In-Jeong Cho, Seung Taek Lim, Jong-In Lee, Airi Han
Journal: Cancer Research (2023)

Abstract Background) Breast cancer is a leading cause of death worldwide. Tumor vascularity is a hallmark of cancer including breast cancer. However, targeting tumor vascularity did not show consistent benefit when applied in clinic. This study aimed to investigate in which group of patients can tumor vascularity be a prognostic factor and how does change of tumor vascularity play in this situation. Materials and methods) Female patients with breast cancer who received preoperative chemotherapy due to breast cancer between 2003 and 2018 at Wonju Severance Hospital, Korea, were included. Clinocopathological characteristics were collected. Hounsfield units(HU) on contrast-enhanced computed tomography(CT) was used as a marker indicating tumor vascularity. Tumor to aortic arch ratio(TAR) of HU on contrast enhanced CT was applied to enhance objectivity of measurement. Patients were categorized according to the cut-off values retrieved from the receiver operating characteristic curve. Kaplan-Meier curves were generated to compare recurrence-free interval (RFI) and overall survival (OS). Results) The final cohort included 162 patients with a mean age of 48.63±7.9 (30-69) years. Initial TAR was 0.38±0.103 (range, 0.184-0.946) and TAR after completion of preoperative systemic treatment was 0.29 0.094(0.677-0.298). Difference between TAR of immediate before surgery and first clinical presentation was -0.0860.094(-0.386 – 0.176). TAR was decreased in 122 (75.3%) patients. Initial TAR was significantly correlated with recurrence free survival(RFS)(p=0.002). However, TAR after preoperative systemic treatment (p=0.221) or delta TAR (area under receiver operating characteristics = 0.498) were not significant. Interestingly, initial TAR was significant only in patients with decreased TAR after preoperative systemic treatment(p=0.005). Conclusion) Tumor vascularity represented with HU was significantly related with patients’ survival only when tumor vascularity was decreased in response to systemic treatment. Considering no antiangiogenic agents were applied as preoperative systemic treatment and still capacity of tumor vascularity as a biomarker was influenced by the change of itself, antiangiogenic agents could be used as a complimentary agent for the other agents which also impact tumor vascularity. Citation Format: Hyang Suk Choi, Eun Ju Son, Hany Hany Noh, In-Jeong Cho In-Jeong Cho, Seung Taek Lim, Jong-In Lee, Airi Han. Performance of tumor vascularity as a biomarker is correlated with the change of tumor vascularity after preoperative systemic treatment in patients with breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-30.
Abstract P2-11-03: How to make decisions in ductal carcinoma in situ? The first study of clinical applicability of the MSKCC ductal carcinoma in situ nomogram in the prediction of local recurrence risk after breast conserving surgery in a Brazilian cohort
Authors: Larissa Marques, Heloísa Carvalho, Filomena Carvalho, Luciana Rodrigues, Fernando Aguiar, Alfredo Barros
Journal: Cancer Research (2023)

Abstract Introduction: Radiation therapy (RT) plays an important role in the management of patients with ductal carcinoma in situ (DCIS) of the breast, treated by breast conserving surgery (BCS). RT reduces significantly the risk of local recurrences (LR). Efforts are being, currently, to de-escalate RT in this scenario with individualized decision-makings. Several biomarkers and clinical tools were developed to predict the probability of LR and aid a tailored clinical decision. The aim of this study is to assess the potential of the MSKCC DCIS Nomogram, which combines clinical, pathologic, and treatment features to forecast LR after BCS for DCIS patients and assist physicians to recommend RT. Methods: Were enrolled into the study women with DCIS undergoing BCS, with clear surgical margins, and external RT from 1993 to 2018 at a specialized breast cancer service in São Paulo, Brazil. The data were collected from medical records. The MSKCC DCIS Nomogram was applied to the study population. Receiver operating characteristic curve were drawn and the area under the curve (AUC) of 10-year risk of LR evaluation was calculated. Results: 110 women were eligible. Eight patients had LR (7,3%), being 5 invasives (62,5%) and 3 in situ (37,5%). The follow-up mean time was 4.8 years. Time to recurrence was 9.6 years with a 10 years risk of LR of 10,3%. The MSKCC DCIS Nomogram 10-year risk estimates showed satisfactory correlation as regard to LR with the AUC of 0.61. The nomogram is warranted for the 10-year risk LR prediction, and it may reinforce RT indication. Conclusions: The MSKCC DCIS Nomogram may identify patients with DCIS treated by BCS with high probability of LR, and therefore is a useful treatment decision aid for patients with DCIS and may assist the RT recommendation. Citation Format: Larissa Marques, Heloísa Carvalho, Filomena Carvalho, Luciana Rodrigues, Fernando Aguiar, Alfredo Barros. How to make decisions in ductal carcinoma in situ? The first study of clinical applicability of the MSKCC ductal carcinoma in situ nomogram in the prediction of local recurrence risk after breast conserving surgery in a Brazilian cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-03.
Abstract OT2-18-01: Nab-paclitaxel followed by dose-dense epirubicin/cyclophosphamide in neoadjuvant chemotherapy for triple-negative breast cancer: an open-label, single-arm phase II study
Authors: Yin Liu, Lei Fan, Zhi-Ming Shao, Zhong-Hua Wang
Journal: Cancer Research (2023)

Abstract Purpose: The anti-tumor activity of nab-paclitaxel followed by epirubicin/cyclophosphamide (EC) as neoadjuvant chemotherapy (NAC) in Asian patients remains unclear, particularly in the aggressive subtype triple-negative breast cancer (TNBC). This study aimed to evaluate the efficacy and safety of this NAC regimen in TNBC. Methods: In this Simon’s two-stage, phase II study, treatment-naïve patients with resectable unilateral primary invasive TNBC were enrolled. Eligible patients received nab-paclitaxel 125 mg/m2 weekly on day 1 for 12 weeks, followed by dose-dense EC (epirubicin 90 mg/m2; cyclophosphamide 600 mg/m2) on day 1 for four 2-week cycles. The primary endpoint was the total pathological complete response (tpCR, ypT0/is ypN0) rate. Secondary endpoints included breast pathological complete response (bpCR, ypT0/is) rate, objective response rate (ORR), the proportion of patients requiring breast-conserving surgery, and safety. Results: 55 eligible patients were enrolled and treated. After neoadjuvant therapy, tpCR and bpCR were respectively observed in 43.1% (95% CI, 29.3%-57.8%) and 49.0% (95% CI, 3)4.8%-63.4%) of 51 evaluable patients for pathological response evaluation. 44 had an ORR as their best response (80.0%; 95% CI, 67.0%-89.6%). No correlations between clinicopathological variables and pathological/clinical response were observed. Grade 3 or more AEs occurred in 63.6% of 55 patients. The most frequent AEs were alopecia. No treatment-related surgical delay or death occurred. Conclusions: Nab-paclitaxel followed by dose-dense EC as NAC demonstrates promising anti-tumor activity and acceptable tolerability for patients with TNBC. Citation Format: Yin Liu, Lei Fan, Zhi-Ming Shao, Zhong-Hua Wang. Nab-paclitaxel followed by dose-dense epirubicin/cyclophosphamide in neoadjuvant chemotherapy for triple-negative breast cancer: an open-label, single-arm phase II study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-18-01.